Muscular dystrophies are X-linked recessive genetic diseases that exhibit muscle fiber degeneration and necrosis as main lesions and cause progressive muscular atrophy.
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are known as the muscular dystrophies.
In particular, “DMD” is a disease that has a high incidence and exhibits severe symptoms. DMD is caused by a deficiency in dystrophin protein due to introduction of a stop codon into an exon of a dystrophin gene by a point mutation or a frame shift mutation.
DMD has an incidence of 1 in 3,500 newborn males. DMD patients show the following clinical symptoms: onset of the disease during early childhood; a loss of ambulation at around 10 years of age; and development of a medical condition leading to death by respiratory failure or heart failure in their 20s. Therefore, it is rare that the DMD patients survive beyond their 30s.
It should be noted that “BMD” is a disease due to a mutation that does not produce a stop codon, and occurs when the dystrophin protein itself is expressed but its structure is abnormal. Symptoms of BMD are milder and less progressive than those of DMD.
Under the present circumstances, there is no effective therapeutic method for such severe DMD. In recent years, however, usefulness of an antisense nucleic acid constructed of a morpholino oligomer (PMO) has attracted attention (see Non Patent Literature 1 and Patent Literature 1).
A therapy using an antisense nucleic acid is a technology involving administering an oligomer having a sequence complementary to a target splicing site to induce sequence-specific exon skipping (read-through of a stop codon resulting from a mutation on an exon) in the dystrophin gene and restore the protein expression.
In addition, when the PMO is used as the antisense nucleic acid, there is an advantage in that the PMO is a very stable substance that is hardly degraded in vivo unlike a normal RNA-based oligomer.
The PMO is a technology that has attracted attention in a therapy for DMD as described above, but has a crucial problem in its clinical use.
The PMO shows extremely low cell permeability. Hence, in order to achieve the clinical application, it is essential to develop means for allowing passage of the PMO through capillary walls, which are present in large amounts in a muscle tissue, to significantly improve introduction efficiency of the PMO into muscle fibers (muscle cells).
At the present stage, a systemic therapy via intravascular administration of the PMO cannot be performed, and thus it is necessary to continuously perform local intramuscular administration, resulting in remarkable reductions in QOL of the patients.
Further, under the present circumstances, the PMO cannot be introduced into muscle fibers (muscle cells) of the heart and diaphragm, which cause heart failure and respiratory distress as immediate causes of death from DMD, respectively.